‘Provocative’ Survival Result in Myelofibrosis Trial

CHICAGO — A randomized trial testing the addition of selinexor (Xpovio) to ruxolitinib (Jakafi) for myelofibrosis only met one of its two primary endpoints, yet the combination also showed a potential survival benefit.

At 24 weeks, a significantly greater proportion of JAK inhibitor-naive patients achieved a 35% or greater reduction in spleen volume with ruxolitinib plus selinexor compared with ruxolitinib plus placebo (50% vs 28%, P<0.0001), reported John Mascarenhas, MD, of the Tisch Cancer Institute at the Icahn School of Medicine at Mount Sinai in New York City.

That improvement did not correlate with a greater improvement in symptoms (the study’s co-primary endpoint), with both arms demonstrating meaningful reductions, said Mascarenhas, and the combination was also associated with more high-grade toxicity.

But with a median follow-up of about 11 months, patients assigned to selinexor plus ruxolitinib had numerically longer overall survival (HR 0.43, 95% CI 0.19-1.00, nominal P=0.022).

“Selinexor and ruxolitinib represent a novel treatment strategy in JAK inhibitor-naive myelofibrosis,” Mascarenhas said during a late-breaking presentation at the American Society of Clinical Oncology (ASCO) meeting.

The combination “achieved a rapid, deep, and sustained spleen volume reduction compared to ruxolitinib alone, and this was consistent across all subgroups,” he said. “Spleen volume reduction, most importantly, was associated with this improved overall survival.”

Findings from the so-called SENTRY trial were simultaneously published in the Journal of Clinical Oncology.

‘Like Déjà Vu All Over Again’

The overall survival benefit was “perhaps the most provocative finding” but warrants continued monitoring, said ASCO discussant Andrew Tucker Kuykendall, MD, of the H. Lee Moffitt Cancer Center and Research Institute in Tampa, Florida.

“The question really — and this is quite blunt — is were more people dying on the ruxolitinib arm than we would expect or were fewer patients dying on the combination arm than we would expect?” he said.

Myelofibrosis is both a hematologic cancer and aggressive inflammatory disease driven by aberrant proliferation of myeloid progenitor cells that leads to scarring in the bone marrow, splenomegaly, anemia, and constitutional symptoms such as fatigue and night sweats. It has a median survival of roughly 4 to 5 years.

JAK inhibitors have become standard of care in myelofibrosis since ruxolitinib’s 2011 approval, but the drug cannot effectively restore hematopoiesis, said Kuykendall, and the depth and duration of response can also be limited due to a lack of specificity toward driver mutations and because of complex disease pathways beyond JAK-STAT.

Previous ruxolitinib combination attempts, including with navitoclax and pelabresib, have also helped reduce spleen volume over single-agent ruxolitinib but without a significant symptom benefit. Neither of those drugs ended up getting approval, though Kuykendall said the regulatory requirement for both spleen and symptom superiority is “dubious.”

“As Yogi Berra said, ‘It’s like déjà vu all over again,’ albeit this time with an already-approved agent,” he said.

Approved for pretreated multiple myeloma, the oral selective inhibitor of exportin 1 (XPO1) selinexor has previously demonstrated activity in myelofibrosis.

Given that selinexor is a commercially available drug, Mascarenhas suggested the SENTRY data could potentially influence National Comprehensive Cancer Center guidelines. Patients with proliferative disease, big spleens or high symptom burden, and with transplant as a goal could represent groups to prioritize in an off-label setting, he said.

Study Details

The double-blind phase III SENTRY trial randomized 353 patients with intermediate- to high-risk myelofibrosis in a 2:1 ratio to 28-day cycles of oral ruxolitinib (twice daily, dosed by platelet count) plus oral selinexor (60 mg, once weekly) or ruxolitinib plus placebo. Treatment was continued until disease progression or unacceptable toxicity. Dual antiemetic prophylaxis was required during the first two cycles to reduce gastrointestinal toxicities.

Patients were stratified by Dynamic International Prognostic Scoring System (DIPSS) risk category, spleen volume, and platelet count at baseline.

The co-primary endpoint for symptoms was measured as an absolute mean change in total symptom score on the Myelofibrosis Symptom Assessment Form version 4.0, excluding fatigue. From an average total score of 22.6 at baseline, both arms showed symptom improvements at 24 weeks (-9.9 in the selinexor arm and -10.9 in the placebo arm).

Participants in the study had a median age of 67 years, two-thirds were white, and 58% were men. Half (51%) had primary myelofibrosis, while 26% developed myelofibrosis following essential thrombocythemia and 23% had post-polycythemia vera myelofibrosis. At baseline, mean spleen volume was over 1,600 cm³, while the DIPSS risk category was intermediate-1 for 56% of patients, intermediate-2 for 35%, and high for 9% of the patients.

Mascarenhas also presented an exploratory analysis showing that a higher proportion in the selinexor group achieved at least a 20% reduction in variant allele frequency (32% vs 24% in the control group), which included the three driver mutations of myelofibrosis — JAK2, MPL, and CALR.

“This supports this relationship between molecular response and clinical outcomes,” he said.

Furthermore, a post hoc analysis showed the combination to be associated with a reduction in circulating peripheral blasts, an adverse prognostic marker.

Some of the adverse events (AEs) more common with selinexor included thrombocytopenia (59% vs 43%), nausea (57% vs 17%), neutropenia (27% vs 9%), fatigue (27% vs 16%), diarrhea (22% vs 15%), dizziness (19% vs 10%), asthenia (16% vs 10%), abdominal pain (15% vs 7%), decreased appetite (15% vs 3%), vomiting (12% vs 5%), and dysgeusia (10% vs 1%).

Grade ≥3 AEs occurred in 70% of the combination arm and 50% of the control arm, with anemia, neutropenia, thrombocytopenia, nausea, and fatigue all higher with selinexor. AEs leading to treatment discontinuation occurred in 15% and 9%, respectively.

Serious AEs were reported in a similar proportion of patients (27% vs 24%), and rates of leukemia transformation were identical, at 1.7% in both arms, said Mascarenhas. AEs leading to death occurred in 0.9% of the selinexor arm and 2.6% of the placebo arm.